Wild mouse species differ from one another and from the various inbred laboratory mouse strains in their susceptibility to the mouse gammaretroviruses and retrovirus-induced diseases. These differences are due to variations in specific host genes, and we have been engaged in an ongoing effort to identify and characterize several mouse genes involved in resistance. Our major focus has been on cell surface virus receptors and the cellular factors that interfere with receptor binding. One area of investigation is focused on a novel virus resistance gene originally found in the Asian wild mouse species M. castaneus. This gene, termed Rmcf2, is responsible for partial resistance to the highly pathogenic polytropic class of leukemia viruses. We demonstrated that this resistance is due to a chromosomally integrated copy of the viral genome, and we have shown that expression of the envelope glycoprotein of this integrated provirus is associated with the virus resistance phenotype. This suggests that Rmcf2 resistance may be mediated through an interference mechanism. We have now identified at least 2 additional resistance genes of the same type in different breeding lines of M. castaneus. This suggests that co-option of proviral envelope genes is an important and common survival strategy in populations exposed to endemic infections. [unreadable] [unreadable] A second study deals with two unusual variants of the ecotropic gammaretroviruses that are cytopathic in M. dunni cells and also have altered host range. These phenotypes are due to different amino acid substitutions at the same site in the two viruses. This substitution alters one of the 3 amino acids that form the cell surface receptor binding site. The fact that these 2 viruses cause cytopathic effects in a cell line with a variant receptor gene suggests that the virus-receptor interaction mediates cytopathicity. This conclusion was confirmed by the observation that cytopathicity due to virus infection is seen in stable transfectants expressing this variant receptor but not in transfectants expressing the prototypical receptor. Because evidence also suggests that cytopathicity is affected by inhibitors of glycosylation, we are currently evaluating the role of glycosylation in virus infectivity and cytopathicity. We have now demonstrated that glycosylation modulates virus entry through both naturally occuring variants of the ecotropic receptor.[unreadable] [unreadable] In a third study, we have screened a panel of cells derived from evolutionarily divergent wild mouse species for infectivity with a panel of mouse gammaretroviruses. These cells show novel patterns of resistance. Analysis of one of these resistance phenotypes shows that the block to virus replication is post entry and targets the viral capsid. These cells are being evaluated for the presence of a novel allele at Fv1, a gene responsible for capsid-mediated resistance in laboratory mice. [unreadable] [unreadable] A fourth study was designed to elucidate the receptor determinants that mediate entry of the polytropic and xenotropic host range classes of gammaretrovirus. We have now identified 4 functional variants of the receptor used by these viruses, termed XPR1, in wild mice. We cloned both genes and analyzed chimeras and mutants to show that 2 of the 4 extracellular loops of this membrane protein contain the determinants for virus entry. We identified two critical amino acids, one in each loop, that independently mediate entry of xenotropic viruses. Analysis of the provirus content of the various wild mouse species suggests that the phenotypic variants of mouse XPR1 likely arose in conjunction with exposure to gammaretrovirus infections and co-evolutionary adaptations in the virus envelope.